DE4224402A1 - New pyridine derivatives with leukotriene-B¶4¶ antagonistic effects - Google Patents

Abstract

The invention pertains to new pyridine derivatives of formula (I) where . &cir& _. &cir& _. &cir& _ denotes a single bond or a double bond, m, n, p and r in each case stands for a number from 0 to 5, q is 1 or 2, U denotes a single bond or the grouping -CH2-CH2-, -CHOH-, -CO- -CH=CH-, -C=C-, -CO-CO- or -CHOH-CHOH-, V stands for a single bond, phenyl residue or pyridyle residue, W is a hydrogen atom, a halogen atom, an alkyl group with up to four carbon atoms, a trifluoromethyl group, an alkylsulfonylamino group, a trifluoromethylsulfonylamino group, an arylsulfonylaminocarbonyl group, a free, esterified or amidated carboxyl group, or a hydroxy group, X denotes a free, esterified or amidated carboxyl group, Y is an oxygen atom or a methylene group, and Z is a single bond if q is 2 or otherwise an alkyl group or alkylene group with at most 8 carbon atoms or a phenyl, phenoxy or styryl residue substituted by alkyl groups with at most 4 carbon atoms, alkoxy groups with at most 4 carbon atoms, 1-oxoalkyl groups with at most 4 carbon atoms, halogen atoms and/or trifluoromethyl groups. The invention also concerns salts of these derivatives with bases which are generally recognized as physiologically safe.

Description

The invention relates to new pyridine derivatives with leukotriene B ₄ -antagonistic activity, a process for their preparation and their use as medicaments.

Leukotriene B ₄ (LTB ₄ )

was discovered by B. Samuelsson and co-workers as a metabolite of arachidonic acid.

The nomenclature of leukotrienes can be found in the following work:

• a) B. Samuelsson et al., Prostaglandins 19, 645 (1980) 17, 785 (1979).
• b) C.N. Serhan et al., Prostaglandins 34, 201 (1987).

The physiological and in particular the pathophysiological significance of leukotriene B ₄ is summarized in some recent work:

• a) The Leukotrienes, Chemistry and Biology eds. L.W. Chakrin, D.M. Bailey, Academic Press 1984,
• b) J.W. Gillard et al., Drugs of the Future 12, 453 (1987).
• c) B. Samuelsson et al., Science 237, 1171 (1987).
• d) CW Parker, Drug Development Research 10, 277 (1987). It follows that LTB _{4 is} an important inflammation mediator for inflammatory diseases in which leukocytes migrate into the diseased tissue. The effects of LTB ₄ are triggered at the cellular level by the binding of LTB ₄ to a specific receptor.

LTB ₄ is known to cause leukocyte adhesion to the blood vessel wall. LTB ₄ is chemotactically active, ie it triggers a directed migration of leukocytes in the direction of a gradient of increasing concentration. In addition, it indirectly changes vascular permeability due to its chemotactic activity, a synergism with prostaglandin E _{2 being} observed. LTB ₄ obviously plays a crucial role in inflammatory, allergic and immunological processes.

Leukotrienes and especially LTB ₄ are involved in skin diseases that are associated with inflammatory processes (increased vascular permeability and edema, cell infiltration), increased proliferation of skin cells and itching, such as eczema, erythema, psoriasis, pruritus and acne. Pathologically elevated leukotriene concentrations are either causally involved in the development of many dermatitis, or there is a connection between the persistence of the dermatitis and the leukotrienes. Significantly increased leukotriene concentrations were measured, for example, in the skin of patients with psoriasis or atopic dermatitis.

Leukotrienes and especially LTB ₄ are also involved in diseases of internal organs for which an acute or chronic inflammatory component has been described; e.g. B. joint diseases (arthritis); Diseases of the respiratory tract (asthma, rhinitis and allergies); inflammatory bowel diseases (colitis); as well as reperfusion damage (to cardiac, intestinal, or kidney tissue) caused by the second pathological occlusion of blood vessels.

Furthermore, leukotrienes and especially LTB _{4 are involved} in the disease in multiple sclerosis and in the clinical appearance of the shock (caused by infections, burns or complications in kidney dialysis or other extracorporeal perfusion techniques).

Leukotrienes and in particular LTB _{4 also} have an influence on the formation of white blood cells in the bone marrow, on the growth of smooth muscle cells, of keratinocytes and of B lymphocytes. LTB ₄ is therefore involved in diseases with inflammatory processes and in diseases with pathologically increased formation and growth of cells.

Diseases with this appearance represent z. B. leukemia or arthereosclerosis. By antagonizing the effects, especially of LTB ₄ , the active ingredients according to the invention and their dosage forms are specific remedies for diseases of humans and animals, in which leukotrienes in particular play a pathological role.

The new pyridine derivatives with leukotriene B ₄ antagonistic activity are characterized by the general formula I.

wherein
· · · Symbolizes a single bond or a double bond,
m, n and r each represent a number from 0 to 5,
q represents the numbers 1 or 2,
U symbolizes a single bond or the grouping -CH ₂ -CH ₂ -, -CHOH-, -CO-, -CH = CH-, -C = C-, -CO-CO- or -CHOH-CHOH-,
V denotes a single bond, a phenyl radical or a pyridyl radical,
W represents a hydrogen atom, a halogen atom, an alkyl group having up to 4 carbon atoms, a trifluoromethyl group, an alkylsulfonylamino group, a trifluoromethylsulfonylamino group, an arylsulfonylaminocarbonyl group, a free, esterified or amidated carboxyl group, or a hydroxyl group,
X symbolizes a free, esterified or amidated carboxyl group,
Y represents an oxygen atom or a methylene group and
Z is a single bond if q is the number 2 or otherwise an alkyl group or alkylene group with a maximum of 8 carbon atoms or one optionally by alkyl groups with a maximum of 4 carbon atoms, alkoxy groups with a maximum of 4 carbon atoms, 1-oxoalkyl groups with a maximum of 4 carbon atoms, halogen atoms and / or trifluoromethyl groups substituted phenyl radical, phenoxy radical or styryl radical, and their salts with physiologically acceptable bases.

As esterified or amidated carboxyl groups of the pyridine derivatives of the general formula I, preference is given to those which differ from physiologically acceptable ones Derive alcohols or amines. Physiologically acceptable alcohols with which the Carboxyl groups can be esterified, for example straight-chain or branched or cyclic, saturated or unsaturated hydrocarbon residues, if desired can be interrupted by an oxygen atom or a nitrogen atom, or with Hydroxy groups, amino groups or carboxyl groups can be substituted, such as Example alkanols (especially those with 1 to 6 carbon atoms) alkenols, alkynols, Cycloalkanols, cycloalkylalkanols, phenylalkanols, phenylalkenols, alkanediols, Hydroxycarboxylic acids, aminoalkenols or alkylaminoalkenols and dialkylaminoalkanols with 1 to 4 carbon atoms in the alkyl radical.

Alcohols which are suitable for the esterification of the carboxyl groups are, for example, those which are methyl-carboxymethyl, ethyl-2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2-carboxylethyl, propyl, allyl, cyclopropylmethyl, isopropyl, 3-hydroxypropyl, propynyl, 3-aminopropyl, butyl, sec-butyl, tert-butyl, butyl (2) -, Cyclobutyl, pentyl, isopentyl, tert-pentyl, 2-methylbutyl, cyclopentyl, hexyl, Cyclohexyl, cyclo-2-enyl, cyclopentylmethyl, heptyl, benzyl, 2-phenylethyl, octyl, Bornyl, isobornyl, menthyl, nonyl, decyl, 3-phenyl-propyl, 3-phenyl-prop-2-enyl, Undecyl or dodecyl. Alcohols suitable for esterification also come those considered to be unstable, i.e. H. esters cleavable under physiological conditions lead, such as 5-hydroxyindane, acyloxymethanols, especially acetoxymethanol, Pivaloyloxymethanol, 5-indanyloxycarbonylmethanol, glycolic acid, dialkylaminoalkanols, especially dimethylaminopropanol, and hydroxyphthalide.

As physiologically acceptable amines with which the carboxyl groups are amidated can, preferably come ammonia, alkylamines, dialkylamines, alkanolamines, Dialkanolamines with 1 to 6 carbon atoms in the alkyl or alkanol radical or five or six-membered N-heterocycles into consideration. Examples of suitable amines are called: the methylamine, the ethylamine, the isopropylamine, the ethanamine, the  Dimethylamine, the diethylamine, the diethanolamine, the pyrrolidine, the piperidine, the Molpholine or the N-methyl-piperazine.

An alkylsulfonylamino group W is preferably understood to mean such a group be derived from an alkyl group with a maximum of 4 carbon atoms. The methylsulfonylamino group may be mentioned as an example.

Under an arylsulfonylaminocarbonyl group, for example Alkylbenzenesulfonylaminocarbonylgruppe with up to 4 carbon atoms in the alkyl radical - such for example the 4-methylbenzenesulfonylaminocarbonyl group - can be understood.

Examples of physiologically acceptable salts of the carboxyl group include the alkali or alkaline earth metal salts, such as the sodium salt or the calcium salt, the ammonium salt, the trihydroxy aminomethane salt, the copper (II) salt, the piperazine salt or the Methyl glucamine salt, as well as the salts of the pyridine derivatives with amino acids.

The following pyridine derivatives are particularly preferred in the context of the present invention:

• a) Pyridine derivatives of the general formula I with X in the meaning given above . . . in the meaning of a single bond and among these in turn those with in in the meaning of the number 0.
• b) pyridine derivatives of the general formula I with Y in the meaning of an oxygen atom, n in the meaning of a number from 1 to 4, q in the meaning of the number 1 and Z in the Meaning of an alkyl group or alkenyl group with a maximum of 8 carbon atoms and among these, in turn, in which X,. . . and m has the meaning given under a) have.
• c) pyridine derivatives of the general formula I with Y in the meaning of an oxygen atom, n in the meaning of a number from 1 to 4, q in the meaning of the number 1 and Z in the The meaning of a possibly by alkyl groups with a maximum of 4 carbon atoms, Alkoxy groups with a maximum of 4 carbon atoms and / or 1-oxoalkyl groups a maximum of 4 carbon atoms of substituted phenyl radical, phenoxy radical or styryl radical and among these in turn those in which X,. . . and m has the meaning given under a) have,
• d) pyridine derivatives of the general formula I with Y in the meaning of an oxygen atom, n in the meaning of a number from 1 to 5 and q in the meaning of the number 2 and under  these in particular those in which X,. . . and m has the meaning given under a) have,
• e) pyridine derivatives of the general formula I with p in the meaning of the number 0, U and V. in the meaning of a single bond and W in the meaning of a hydrogen atom or a halogen atom (especially a bromine atom or iodine atom) and among them again those in which X, Y, z, p, q,. . . n and m are those mentioned under b), c) or d) Have meaning and
• f) pyridine derivatives of the general formula I with p, U and V in the above Meaning and W in the meaning of a hydrogen atom or a free, esterified or amidated carboxyl group and especially those in which X, Y, p, q,. . . n and m have the meaning given under b), c) or d).

The invention further relates to a process for the preparation of the pyridine derivatives general formula I, which is characterized in that in known per se wise

• a) for the preparation of pyridine derivatives of the general formula I with Y in the meaning of an oxygen atom, a compound of the general formula II wherein m, p, r, U, V, W and X have the meaning given above in the presence of bases with a compound of the general formula III or IVQ- (CH₂) _n -Z ′ (III) Q- (CH₂) _n - Q (IV) where
  n has the meaning given above,
  Z 'means the same as Z, but does not represent a single bond and
  Q represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group, condenses, or
• b) for the preparation of pyridine derivatives of the general formula I with U in the meaning of a grouping -CO-, -CH = CH-, -C = C-, -CO-CO- or -CHOH-CHOH- a compound of the general formula V wherein
  · · · , M, n, p, q, X, Y and Z have the meaning given above and Q 'represents a halogen atom or a trifluoromethanesulfonyloxy group, with a compound of the formula VI, VII or VIII wherein
  p, r, V and W have the meaning given above and
  R 'represents lower alkyl radicals with a maximum of 4 carbon atoms, or
• c) for the preparation of pyridine derivatives of the general formula I with U in the meaning of the grouping -CH = CH- a compound of the general formula IX wherein
  · · · , M, n, q, X, Y and Z have the meaning given above, with a compound of the general formula XW- (CH₂) _r -V- (CH₂) _p -CH₂-P (C₆H₅) ₃ + Br - (X) in which, p, r, V and W have the abovementioned meaning, condenses and, if appropriate, oxidizes an existing triple bond, reduces existing oxo groups, hydrogenates existing multiple bonds, alkylates existing hydroxyl groups, saponifies existing ester groups and / or esterifies existing carboxyl groups or in transferred their amides or salts.

The inventive method according to variant a) is under the conditions carried out, which is conventional for the alkylation of aromatic or heteroaromatic hydroxy compounds used. So you can, for example Compounds of formula II in an inert solvent in the presence of alkali metal carbonates, such as potassium carbonate or cesium carbonate (J. Chem. Soc., Chem. Comm. 1979, 285) alkylate with the compounds of the general formula III or IV, where in the latter case pyridine derivatives of the general formula I with q in the meaning of Number 2 receives. The synthesis according to process variant b) is also carried out in a manner known per se Way, for example by making the compounds of formula V in the presence of organic Palladium catalysts with the compounds of formula VI, VII or VIII (Tetrahedron Letters 50, 1975, 4467 ff, Bull. Chem. Soc. Jpn. 60, 1987, 767 ff; Angewandte Chemie 99, 1987, 1285 ff, Tetrahedron Letters 26, 1985, 2667 ff).

The process according to variant c) is carried out under the conditions which one commonly used in the so-called Wittig reactions (Chem. Ber. 94, 1961, 1373f).  

The oxidation of the compounds of general formula I with U in the meaning of a -C = C grouping to compounds with U meaning a -CO-CO grouping takes place according to the method of Seebach (Helv. Chim. Acta. 71, 1988, 237 ff).

The conditions under which the subsequent reactions that may follow are so conventional that they require no further explanation.

The starting compounds required for the process according to the invention can also be used can be synthesized in a manner known per se, for example by using the above conditions mentioned the desired side chains based on the corresponding substituted halopyridines, pyridine aldehydes or with trifluoromethanesulfonic acid esterified hydroxypyridines.

For example, the pyridine derivatives of the general formula II with U in the meaning of a -C = C- or -CH ₂ -CH ₂ group can be prepared by using a compound of the general formula XI

wherein
· · · , M, X and Q 'have the meaning given above, with a compound of the general formula XII

W- (CH₂) _r -V- (CH₂) _p -C≡CH (XII)

where p, r, V and W have the meaning given above and, if appropriate, the Triple bond hydrogenated.

The new pyridine derivatives are pharmacologically active compounds which are particularly notable for their leukotriene-B ₄ antagonistic activity.

The pyridine derivatives of the general formula I are therefore anti-inflammatory, anti-allergic and anti-proliferative.  

The compounds of formula I are particularly suitable for topical application because they a dissociation between desired topical effectiveness and undesirable have systemic side effects.

The new pyridine derivatives of the formula I are suitable in combination with those in the galenic pharmacy usual auxiliaries and vehicles for the local treatment of Skin disorders in which leukotrienes play an important role, such as Contact dermatitis, various types of eczema, neurodermatosis, erythroderma, Pruritis vulvae et ani, rosacea, erythematosus cutaneus, psoriasis, lichen planus et verrucosus and similar skin diseases.

The pharmaceutical specialties are prepared in the usual way by the Active ingredients with suitable additives in the desired application form, such as: Solutions, lotions, ointments, creams or plasters, transferred.

In the pharmaceuticals formulated in this way, the active ingredient concentration depends on the form of administration dependent. For lotions and ointments, an active ingredient concentration of 0.0001% to 3% used.

In addition, the new compounds are optionally in combination with the usual ones Carriers and auxiliaries are also well suited for the production of inhalants, which are used to treat allergic diseases of the respiratory tract such as the Brochial asthma or rhinitis can be used.

The new pyridine derivatives are also suitable in the form of capsules, tablets or dragées, which preferably contain 0.1 to 100 mg of active ingredient or are administered orally, or in the form of suspensions, which preferably contain 1-200 mg of active ingredient per dose unit and rectally are also applied for the treatment of diseases of internal organs in which leukotrienes play an important role, such as. B. allergic diseases of the intestinal tract, such as ulcerative colitis and granulomatous colitis. The new leukotriene B ₄ antagonists are also suitable for the treatment of multiple sclerosis and the symptoms of shock.

In these application forms, the new LTB ₄ antagonists are suitable not only for treating diseases of internal organs with inflammatory processes, but also for treating diseases with increased growth and the formation of cells in which leukotrienes play an important role. Examples are leukemia (increased growth of white blood cells) or arthereosclerosis (increased growth of smooth muscle cells from blood vessels).

The new pyridine derivatives can also in combination, such as. B. with lipoxygenase inhibitors, cyclooxygenase inhibitors, prostacyclin agonists, thromboxane antagonists, leukotriene D ₄ antagonists, leukotriene E ₄ antagonists, leukotriene F ₄ antagonists, phosphodiesterase inhibitors, calcium antagonists, PAF antagonists, glucocorticoids, or other known forms of therapy, or other known forms of therapy.

The following exemplary embodiments serve to explain the inventive method and the process products obtained thereby.

example 1 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionic acid

A. 152.6 g of potassium carbonate and 15.3 g of cesium carbonate are added to a solution of 122 g of 3-hydroxy-2-iodopyridine and 65.7 ml of benzyl bromide in 1.5 l of dimethylformamide, and the suspension is stirred under an argon atmosphere at room temperature for 20 hours . The reaction mixture is filtered, the filter residue is washed with dichloromethane, the filtrate is concentrated and the residue is chromatographed on silica gel with hexane / 10-20% ethyl acetate. 146.3 g of 3-benzyloxy-2-iodopyridine are obtained as an oil.
IR (CHCl ₃ ): 2980, 1552, 1438, 1402, 1371, 1067, 1002, 908 cm ^-1

B. To a solution of 70 g of 3-benzyloxy-2-iodopyridine and 39.8 ml of methyl acrylate in 120 ml of dimethylformamide, 5.2 g of palladium-II-acetate, 77.8 g of potassium carbonate and 72.5 g of tetrabutylammonium bromide are added and the Suspension stirred under an argon atmosphere for 10 hours at 100 ° C (bath temperature). The reaction mixture is concentrated in vacuo, the residue is poured into water and extracted with ethyl acetate. The organic phase is washed three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated. The crude product is chromatographed on silica gel with hexane / 10-25% ethyl acetate. 48.2 g of methyl 3- (3-benzyloxy-2-pyridyl) - (2E) -2-propenate are obtained as an oil.
IR (CHCl ₃ ): 2955, 1708, 1640, 1577, 1440, 1310, 1167, 1110, 988 cm ^-1

C. A solution of 11.5 g of methyl 3- (3-benzyloxy-2-pyridyl) - (2E) -2-propenate in 125 ml of methanol in the presence of 1.15 g of 10% palladium catalyst on activated carbon is placed in the autoclave hydrogenated at an initial pressure of 32 bar for 2 hours at room temperature. The reaction mixture is filtered, the filter residue is washed with methanol and the filtrate is concentrated. 6.8 g of methyl 3- (3-hydroxy-2-pyridyl) propionate of melting point 94-96 ° C. are obtained.
IR (CHCl ₃ ): 2955, 1710, 1600, 1580, 1444, 1320, 1285, 1172, 1108, 1040, 986, 953, 912, 860 cm ^-1

D. To a solution of 300 mg of methyl 3- (3-hydroxy-2-pyridyl) propionate and 450 mg of (1E) -6-bromo-1- (4-methoxyphenyl) -1-hexene in 6 ml of dimethylformamide 1, Added 02 g of cesium carbonate and the suspension was stirred under an argon atmosphere for 20 hours at room temperature. The reaction mixture is filtered, the filter residue is washed with dichloromethane and the filtrate is concentrated. The residue is poured into water, shaken with ethyl acetate, the organic phase washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated. The crude product is purified by high pressure liquid chromatography on reversed phase silica gel (Nova-Pak HR C18) with methanol / water = 8/2. 280 mg of methyl 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionate are obtained as a colorless oil.
IR (KBr): 2938, 2840, 1745, 1610, 1590, 1575, 1512, 1450, 1285, 1246, 1204, 1160, 1119, 1040, 960, 840, 810 cm ^-1

The preparation of the (1E) -6-bromo-1- (4-methoxyphenyl) -1- used in Example 1 D Hexen is described in German patent application P 40 28 866.

E. A solution of 130 mg of 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} - propionic acid methyl ester in 6.5 ml of methanol is mixed with 6.5 ml of 2N Sodium hydroxide solution added and stirred for 20 hours at room temperature. The methanol is removed in vacuo, the alkaline solution is acidified to pH 5 with 2N sulfuric acid, shaken out with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated. 107 mg of the title compound are obtained as a colorless oil.
IR (KBr): 2940, 1713, 1608, 1578, 1575, 1512, 1447, 1285, 1249, 1228, 1180, 1119, 1072, 1033, 965, 844, 810 cm ^-1

Example 2 3- {3- [3- (4-Acetvl-3-methoxy-2-propylphenoxy) propoxy] -2-pyridyl} propionic acid

A. To a solution of 764 mg of 3- (3-hydroxy-2-pyridyl) propionic acid methyl ester and 2 g of 2-hydroxy-4- (3-iodopropoxy) -3-propylacetophenone (J. Med. Chem. 1989, 32, 1145) in 33 ml of dimethylformamide, 1.34 g of potassium carbonate are added and the suspension is stirred under an argon atmosphere at 70 ° C. for 6 1/2 hours. The reaction mixture is filtered, the filter residue is washed with ethyl acetate and the filtrate is concentrated. The residue is poured into water, shaken with ethyl acetate, the organic phase washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated. The crude product is chromatographed on silica gel with hexane / 0-20% ethyl acetate. 1.12 g of methyl 3- {3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -2-pyridyl} propionate of melting point 85-87 ° C. are obtained.
IR (CHCl ₃ ): 2950, 2865, 1725, 1623, 1442, 1368, 1266, 1115, 1055, 985 cm ^-1

B. Under the conditions of Example 2A, 600 mg of methyl 3- {3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propoxy] -2-pyridyl} propionate are used in the presence of 940 mg of cesium carbonate Potassium carbonate reacted with 205 mg iodomethane, processed and the crude product chromatographed on silica gel with hexane / 0-10% ethyl acetate. 570 mg of methyl 3- {3- [3- (4-acetyl-3-methoxy-2-propylphenoxy) propoxy] -2-pyridyl} propionate are obtained as an oil.
IR (film): 2950, 2865, 1730, 1668, 1585, 1440, 1404, 1352, 1260, 1210, 1110, 1004, 990, 793 cm ^-1

C. A solution of 200 mg of methyl 3- {3- [3- (4-acetyl-3-methoxy-2-propylphenoxy) propoxy] -2-pyridyl} propionate in 1 ml of methanol is mixed with 1.8 ml of 2N Sodium hydroxide solution was added and the mixture was stirred at 50 ° C. for 3 hours. The reaction solution is prepared analogously to Example 1E and 148 mg of the title compound are thus obtained as a light yellow oil.
IR (film): 2960, 2930, 2870, 1727, 1670, 1586, 1445, 1410, 1354, 1268, 1212, 1185, 1113, 1055, 800 cm ^-1

Example 3 3- {6-iodo-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionic acid

A. A solution of 15 g of methyl 3- (3-hydroxy-2-pyridyl) propionate in 250 ml of methanol is mixed with 12.4 g of sodium iodide, cooled to 15 ° C. and 74 ml of aqueous sodium hypochlorite solution (6.5% active chlorine ) added dropwise. The yellow suspension is evaporated down, the residue is taken up in water, acidified to pH 4 with 2N sulfuric acid and extracted with ethyl acetate. The organic phase is washed with 10% sodium thiosulfate solution, dried with sodium sulfate, concentrated and the residue is chromatographed on silica gel with hexane / 0-50% ethyl acetate. 8.3 g of methyl 3- (3-hydroxy-6-iodo-2-pyridyl) propionate of melting point 145-148 ° C. are obtained.
IR (CHCl ₃ ): 2958, 1710, 1590, 1435, 1410, 1370, 1260, 1172, 1112, 1095, 984 cm ^-1

B. Under the conditions of Example 1D, 850 mg of methyl 3- (3-hydroxy-6-iodo-2-pyridyl) propionate with 612 mg of (1E) -6-bromo-1- (4-methoxyphenyl) -1-hexene implemented, processed and the crude product chromatographed on silica gel with hexane / 0-5% ethyl acetate. 773 mg of methyl 3- {6-iodo-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionate are obtained as a colorless oil.
IR (CHCl ₃ ): 2940, 1725, 1604, 1570, 1505, 1431, 1171, 1118, 1100, 1025, 962 cm ^-1

C. A solution of 460 mg of 3- {6-iodo-3- [6- (4-methoxyphenyl- (5E) -5-hexenyloxy] -2-pyridyl} propionic acid methyl ester in 5 ml of methanol and 5 ml of tetrahydrofuran is mixed with 3 ml of 1N sodium hydroxide solution was added and the mixture was stirred at room temperature for 20 hours, the methanol was distilled off in vacuo, the alkaline solution was acidified to pH 3 with 2N sulfuric acid, extracted with ethyl acetate, the organic phase was dried over sodium sulfate and concentrated to give 446 mg of the title compound obtained as a light yellow solid with a melting point of 95-97 ° C.
IR (CHCl ₃ ): 2940, 1720, 1608, 1572, 1510, 1433, 1175, 1123, 1100, 1028, 965 cm ^-1

Example 4 3- {6-Acetyl-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionic acid

A. A solution of 495 mg of 3- {6-iodo-3- [6- (4-methoxyphenyl- (5E) -5-hexenyloxy] -2-pyridyl} propionic acid methyl ester and 397 mg of ethoxyvinyltributyltin in 2 ml of toluene is mixed with 30 mg of bis-triphenylphosphine-palladium-II-chloride were added and the mixture was heated with stirring for six hours at 110 ° C. The reaction mixture was filtered through diatomaceous earth, the filter residue was washed with diethyl ether, 1.5 ml of 2N hydrochloric acid were added to the filtrate, and the mixture was stirred for 4 hours The organic phase is separated off, dried with sodium sulfate and concentrated, and 95 mg of 3- {6-acetyl-3- [6- (4-methoxyphenyl- (5E) -5-hexenyloxy] -2-pyridyl} - Get methyl propionate as an oil.
IR (CHCl ₃ ): 2930, 1725, 1680, 1604, 1568, 1506, 1450, 1359, 1171, 1118, 1097, 1028, 963, 830 cm ^-1

B. Under the conditions of Example 1E, a solution of 90 mg of 3- {6-acetyl-3- [6- (4-methoxyphenyl- (SE) -5-hexenyloxy] -2-pyridyl} propionic acid methyl ester in 1 ml of methanol Saponified with 0.7 ml of 2N sodium hydroxide solution and processed, 73 mg of the title compound of melting point 89-90 ° C. are obtained.
IR (KBr): 2970, 2925, 1710, 1688, 1610, 1572, 1518, 1460, 1362, 1325, 1254, 1222, 1179, 1122, 1042, 963, 840, 820, 598 cm ^-1

Example 5 5- {2- (2-Carboxyethyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6-pyrid-yl} -4- pentic acid

A. To a solution of 300 mg of 3- {6-iodo-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionate and 68 mg of 4-pentynate in 5 ml Triethylamine 11 mg of bis-triphenylphosphine-palladium-II-chloride and 1.5 mg of copper-I-iodide are added and the mixture is stirred at room temperature for 20 hours. The reaction mixture is filtered, the filter residue is washed with ethyl acetate and the filtrate is concentrated. The residue is taken up in water, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The crude product is chromatographed on silica gel with hexane / 0-10% ethyl acetate and subjected to complete purification of the high pressure liquid chromatography on reversed phase silica gel (Nova-Pak HR C18) with acetonitrile / water = 75/25. 280 mg of 5- {2- (2-methoxycarbonylethyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6-pyridyl} -4-pentic acid methyl ester are obtained as a colorless oil.
IR (CHCl ₃ ): 2925, 2850, 1730, 1607, 1572, 1509, 1450, 1438, 1364, 1300, 1172, 1114, 1029, 964 cm ^-1

B. Under the conditions of Example 1E, a solution of 90 mg of 5- {2- (2-methoxycarbonylethyl) -3- [6-4-methoxyphenyl- (5E) -5-hexenyloxy] -6-pyridyl} -4 -pentic acid methyl ester in 3 ml of methanol and 1 ml of tetrahydrofuran with 3 ml of 2N sodium hydroxide solution and prepared. 65 mg of the title compound of melting point 89-91 ° C. are obtained.
IR (KBr): 3420 (broad), 2930, 1732, 1705, 1602, 1570, 1508, 1456, 1305, 1242, 1175, 1120, 1030, 805 cm ^-1

Example 6 3- {6- [2- (3-carboxyphenyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} - propionic acid

A. Under the conditions of Example 5A, 1 g of methyl 3- {6-iodo-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionate with 320 mg of 3-ethynylbenzoic acid Acid methyl ester reacted, processed and the crude product chromatographed on silica gel with hexane / 0-15% ethyl acetate. 835 mg of methyl 3- {6- [2- (3-methoxycarbonylphenyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionate are obtained as an oil .
IR (CHCl ₃ ): 2943, 1718, 1604, 1571, 1505, 1448, 1285, 1170, 1102, 1028, 962 cm ^-1

B. Under the conditions of Example 3C, 70 mg of 3- {6- [2- (3-methoxycaibonyl phenyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2 -pyridyl -} - propionic acid methyl ester in 3 ml of methanol with 3 ml of 2N sodium hydroxide solution and prepared. 56 mg of the title compound of melting point 76-79 ° C. are obtained.
IR (KBr): 2925, 2848, 2220, 1705, 1690, 1608, 1575, 1515, 1548, 1358, 1290, 1242, 1180, 1117, 1040, 828, 818, 758 cm ^-1

Example 7 3- {6- [2- (4-carboxyphenyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionic acid

A. Under the conditions of Example 5A, 1 g of methyl 3- {6-iodo-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionate with 384 mg of 4-ethynylbenzoic acid Acid methyl ester reacted, processed and the crude product chromatographed on silica gel with hexane / 0-7% ethyl acetate. 670 mg of methyl 3- {6- [2- (4-methoxycarbonylphenyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionate are obtained as an oil .
IR (CHCl ₃ ): 2943, 2835, 2200, 1715, 1602, 1568, 1504, 1445, 1273, 1170, 1108, 1013, 963, 852, 820 cm ^-1

B. Under the conditions of Example 3C, 600 mg of 3- {6- [2- (4-methoxycarbonylphenyl) -ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2 -pyridyl -} - methyl propionate in 4 ml of methanol and 2 ml of tetrahydrofuran with 4 ml of 2N sodium hydroxide solution and prepared. 548 mg of the title compound of melting point 153-156 ° C. are obtained.
IR (KBr): 2930, 2200, 1718, 1674, 1600, 1565, 1507, 1450, 1420, 1312, 1285, 1240, 1172, 1110, 964, 860, 770 cm ^-1

Example 8 3- {6- [2- (4-carboxyphenyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexeny-loxy] -2-pyridyl} - propionic acid bis-tris (hydroxymethyl) aminomethane salt

A solution of 200 mg of 3- {6- [2- (4-carboxyphenyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) - 5-hexenyloxy] -2-pyridyl} propionic acid in 24 ml of acetonitrile is heated to 80 ° C. and 0.152 ml of a solution of 8.225 g of tris (hydroxymethyl) aminomethane in 15 ml of water is added. The mixture is stirred for one hour at 80 ° C, one hour at 55 ° C, three hours at 45 ° C and 48 hours at room temperature. The crystals are suctioned off and dried in vacuo. 218 mg of the title compound of melting point 108-110 ° C. are obtained.
IR (KBr): 3300 (broad), 2930, 2205, 1603, 1575, 1508, 1450, 1385, 1245, 1172, 1110, 1060, 1028, 965, 785 cm ^-1

Example 9 3- {6- [2- (4-carboxyphenyl) ethynyl] -3-decyloxy-2-pyridyl} propionic acid

A. Under the conditions of Example 5A, 6.3 g of methyl 3- (3-hydroxy-6-iodo-2-pyridyl) propionate are reacted with 3.28 g of methyl 4-ethynyl benzoate, processed, and the crude product on silica gel with hexane / 0 -50% ethyl acetate chromatographed. 4.1 g of methyl 3- {3-hydroxy-6- [2- (4-methoxycarbonylphenyl) -ethynyl] -2-pyridyl} propionate of melting point 173-177 ° C. are obtained.
IR (CHCl ₃ ): 2950, 1718, 1710, 1604, 1452, 1435, 1365, 1300, 1277, 1104, 1015, 965, 855, 835 cm ^-1

B. Under the conditions of Example 1D, 500 mg of methyl 3- {3-hydroxy-6- [2- (4-methoxycarbonylphenyl) -ethynyl] -2-pyridyl} propionate are reacted with 358 mg of 1-decyl bromide and processed. 531 mg of methyl 3- {6- [2- (4-methoxycarbonylphenyl) -ethynyl] -3-decyloxy-2-pyridyl} propionate of melting point 88-90 ° C. are obtained.
IR (CHCl ₃ ): 2930, 2860, 1720, 1608, 1575, 1450, 1310, 1279, 1112, 1020, 860 cm ^-1

C. Under the conditions of Example 3C, 372 mg of methyl 3- {6- [2- (4-methoxycarbonylphenyl) -ethynyl] -3-decyloxy-2-pyridyl} propionate in 1.6 ml of methanol and 5 ml of tetrahydrofuran 2.2 ml of 1N sodium hydroxide solution saponified and processed. 190 mg of the title compound of melting point 167 ° C. are obtained.
IR (KBr): 2920, 2850, 2210, 1708, 1690, 1605, 1672, 1450, 1420, 1285, 1243, 1171, 1112, 1019, 860, 832, 770 cm ^-1

Example 10 3- {6- [2- (4-carboxyphenyl) ethynyl] -3- [3- (4-acetyl-3-methoxy-2-propylphe-noxy) propoxy] - 2-pyridyl} propionic acid

A. Under the conditions of Example 2A, 1 g of methyl 3- {3-hydroxy-6- [2- (4-methoxycarbonylphenyl) -ethynyl] -2-pyridyl} propionate is mixed with 1.39 g of 2-hydroxy-4- (3-iodopropoxy) -3-propylacetophenone reacted, processed and the crude product chromatographed on silica gel with hexane / 0-10% ethyl acetate. 1.48 g of 3- {6- [2- (4-methoxycarbonylphenyl) -ethynyl] -3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -p-ropoxy] -2- pyridyl} -propionic acid methyl ester of melting point 71-73 ° C.
IR (CHCl ₃ ): 2960, 2878, 1722, 1675, 1627, 1608, 1575, 1500, 1450, 1370, 1270, 1116, 1060, 1018, 858, 826 cm ^-1

B. Under the conditions of Example 2B, 1.4 g of 3- {6- [2- (4-methoxycarbonylphenyl) ethynyl] -3- [3- (4-acetyl-3-hydioxy-2-propylphenoxy-pr -opoxy] -2-pyridyl} - methyl propionate is reacted with 345 mg iodomethane and processed, 1.28 g of 3- {6- [2- (4-methoxycarbonylphenyl) -ethynyl] -3- [3- (4-acetyl -3-methoxy-2-propylphenoxy-propoxy] -2-pyridyl} -propionic acid methyl ester obtained as a yellow oil.
IR (film): 2955, 2875, 2218, 1723, 1672, 1604, 1588, 1450, 1410, 1360, 1274, 1112, 1058, 1018, 858, 770, 695 cm ^-1

C. Under the conditions of Example 3C, 1.2 g of 3- {6- [2- (4-methoxycarbonylphenyl) -ethynyl] -3- [3- (4-acetyl-3-methoxy-2-propylphenoxy) - propoxy] - 2-pyridyl} - methyl propionate in 20 ml of methanol with 14 ml of 2N sodium hydroxide solution and processed. 1.1 g of the title compound of melting point 134-135 ° C. are obtained.
IR (KBr): 2960, 2880, 2215, 1705, 1680, 1608, 1590, 1458, 1415, 1360, 1275, 1222, 1120, 1060, 1020, 860, 830, 675 cm ^-1

Example 11 3- {6- [2- (4-carboxyphenyl) ethynyl] -3 - [(3RS) -3,7-dimethyl-6-octenyloxy] - 2-pyridyl} - propionic acid

A. Under the conditions of Example 1D, 500 mg of 3- {3-hydroxy-6- [2- (4-methoxycarbonylphenyl) -ethynyl] -2-pyridyl} -propionic acid methyl ester with 354 mg of 1-bromo- (3RS) -3 , 7-dimethyl-6-octene, processed and the crude product chromatographed on silica gel with hexane / 0-10% ethyl acetate. There are 522 mg of methyl 3- {6- [2- (4-methoxycarbonylphenyl) -ethynyl] -3 - [(3RS) -3,7-dimethyl-6-octe-nyloxy] -2-pyridyl} propionate as a yellow oil receive.
IR (film): 2950, 2920, 2218, 1722, 1604, 1572, 1510, 1448, 1310, 1172, 1110, 1015, 858, 830, 770, 695 cm ^-1

B. Under the conditions of Example 3C, 500 mg of 3- {6- [2- (4-methoxycarbonylphenyl) -ethynyl] -3 - [(3RS) -3,7-dimethyl-6-octenyloxy] -2-pyride -yl} -pro pionsäuremethylester in 10 ml of methanol with 7.2 ml of 2N sodium hydroxide solution and prepared. 437 mg of the title compound of melting point 154-156 ° C. are obtained.
IR (KBr): 2920, 2215, 1718, 1685, 1607, 1575, 1458, 1422, 1280, 1252, 1200, 1175, 1120, 1002, 860, 840, 770 cm ^-1

Example 12 3- {3- [6- (4-Methoxyphenyl) - (5E) -5-hexenyloxy] -6- (2-phenylethynyl) -2-pyridyl} -pro pionic acid methyl ester

A. Under the conditions of Example 5A, 500 mg of methyl 3- {6-iodo-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionate are reacted with 102 mg of phenylacetylene, processed and the crude product chromatographed on silica gel with hexane / 0-7% ethyl acetate. 265 mg of methyl 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- (2-phenylethynyl) -2-pyridyl} -propionate are obtained as an oil.
IR (film): 2955, 2840, 1738, 1605, 1575, 1510, 1450, 1282, 1245, 1175, 1115, 1035, 965, 825, 760, 690 cm ^-1

B. Under the conditions of Example 3C, 260 mg of methyl 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- (2-phenylethynyl) -2-pyridyl} propionate are added in 2 , 5 ml of methanol and 2.5 ml of tetrahydrofuran with 5 ml of 1N sodium hydroxide solution and prepared. 201 mg of the title compound of melting point 121-123 ° C. are obtained.
IR (KBr): 2950, 2920, 2840, 2220, 1710, 1605, 1577, 1510, 1450, 1350, 1285, 1253, 1220, 1180, 1113, 962, 760 cm ^-1

Example 13 3- {6- [2- (3-carboxyphenyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2- pyridyl} propionic acid, bis-tris (hydroxymethyl) aminomethane salt

Under the conditions of Example 8, 3- {6- [2- (3-carboxyphenyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionic acid reacted with tris (hydroxymethyl) aminomethane and processed. 250 mg of the title compound of melting point 104-108 ° C. are obtained.
IR (KBr): 3250 (wide), 2940, 2220, 1640, 1604, 1580, 1550, 1510, 1450, 1390, 1300, 1244, 1183, 1115, 1060, 960, 845, 808, 760, 680 cm ^-1

Example 14 3- {6- [2- (4-carboxyphenyl) ethyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2- pyridyl} propionic acid

A. A solution of 300 mg of methyl 3- {3-hydroxy-6- [2- (4-methoxycarbonylphenyl) -ethynyl] -2-pyridyl} -propionate in 3 ml of methanol is prepared in the presence of 30 mg of 10% palladium catalyst hydrogenated on activated carbon at normal pressure and room temperature until two equivalents of hydrogen have been absorbed. The reaction mixture is filtered, the filter residue is washed with methanol and the filtrate is concentrated. 290 mg of methyl 3- {6- [2- (4-methoxycarbonylphenyl) ethyl] -3-hydroxy-2-pyridyl} propionate of melting point 137-139 ° C. are obtained.
IR (CHCl ₃ ): 3320 (broad), 2950, 1710, 1612, 1468, 1440, 1370, 1284, 1180, 1110, 1022, 970 cm ^-1

B. Under the conditions of Example 1D, 280 mg of 3- {6- [2- (4-methoxycarbonylphenyl) ethyl] -3-hydroxy-2-pyridyl} -piopionic acid methyl ester with 220 mg (1E) -6-bromo- 1- (4-methoxyphenyl) -1-hexene reacted, processed and the crude product chromatographed on silica gel with hexane / 0-10% ethyl acetate. There are 230 mg of 3- {6- [2- (4-methoxycarbonylphenyl) ethyl] -3- [6- (4-methoxy phenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionic acid from the melting point Get 59-61 ° C.
IR (CHCl ₃ ): 2945, 1715, 1608, 1580, 1510, 1460, 1435, 1283, 1175, 1115, 1020, 968 cm ^-1

C. Under the conditions of Example 3C, 210 mg of 3- {6- [2- (4-methoxycarbonylphenyl) ethyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2 -p-yridyl} - methyl propionate in 5.4 ml of methanol and 1 ml of tetrahydrofuran with 2.7 ml of 2N sodium hydroxide solution and prepared. 153 mg of the title compound of melting point 135-138 ° C. are obtained.
IR (KBr): 3430 (broad), 2950, 1695, 1608, 1580, 1510, 1460, 1420, 1240, 1178, 1117, 1038, 965, 842, 820, 760 cm ^-1

Example 15 1,10-bis- {2- (2-carboxyethyl) -6- [2- (4-carboxyphenyl) ethynyl] -3-pyridyloxy} decane

A. Under the conditions of Example 1D, 500 mg of methyl 3- {6- [2- (4-methoxycarbonylphenyl) -ethynyl] -3-hydroxy-2-pyridyl} -propionate are reacted with 221 mg of 1,10-dibromodecane and processed and the crude product is stirred out with methanol. After the crystals have been suctioned off and dried, 420 mg of 1, 10-bis- {2- (2-methoxycarbonylethyl) -6- [2- (4-methoxycarbonylphenyl) -ethynyl] -3-pyridyl oxy} -decane of melting point 143 -145 ° C obtained.
IR (CHCl ₃ ): 2940, 2860, 1722, 1608, 1574, 1452, 1310, 1280, 1112, 1020, 860 cm ^-1

B. Under the conditions of Example 3C, 410 mg of 1,10-bis- {2- (2-methoxycarbonylethyl) -6- [2- (4-methoxycarbonylphenyl) ethynyl] -3-pyridyloxy} decane in 11 ml Methanol and 25 ml of tetrahydrofuran are saponified with 5.3 ml of 2N sodium hydroxide solution and processed. The crude product is stirred with methanol, the crystals are suctioned off and dried in vacuo. 360 mg of the title compound of melting point <300 ° C. are obtained.
IR (KBr): 3430 (wide), 2930, 2850, 2220, 1700, 1605, 1575, 1450, 1420, 1283, 1255, 1165, 1117, 1018, 860, 830, 770, 678, 620 cm ^-1

Example 16 5- {2- (2-Carboxyethyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6-pyrid-yl} -5-oxo pentanoic acid

A. Under the conditions of Example 1D, 10 g of 3-hydroxy-2-iodo-6-methylpyridine are reacted with 2.7 ml of iodomethane and processed. 10.5 g of 2-iodo-3-methoxy-6-methylpyridine with a melting point of 45-50 ° C. are obtained.
IR (CHCl ₃ ): 2970, 2920, 2820, 1586, 1554, 1460, 1425, 1360, 1284, 1254, 1139, 1070, 1012.990, 852 cm ^-1

B. A solution of 22 g of 2-iodo-3-methoxy-6-methylpyridine in 880 ml of water is mixed with 70 g of potassium permanganate in portions at 70 ° C. for 5 hours. The reaction mixture is then stirred at 80-90 ° C. for 16 hours, filtered hot, the filter residue is washed with a hot mixture of methanol / water = 1/1, the filtrate is evaporated in half, extracted with ethyl acetate and the water phase is dissolved in 2N hydrochloric acid acidified pH 2. The crystals are suctioned off and dried in vacuo. 11.5 g of 2-iodo-3-methoxy-pyridine-6-carboxylic acid with a melting point of 213-216 ° C. are obtained.
IR (CHCl ₃ ): 3330 (broad), 3030, 3005, 2970, 1760, 1560, 1460, 1420, 1377, 1355, 1260, 1121, 1065, 1010, 925, 843 cm ^-1

C. Under the conditions of Example 1D, 9.8 g of 2-iodo-3-methoxy-pyridine-6-carboxylic acid are reacted with 2.5 ml of iodomethane and processed. 7.4 g of 2-iodo-3-methoxypyridine-6-carboxylic acid methyl ester of melting point 175-178 ° C. are obtained.
IR (CHCl ₃ ): 2992, 2950, 2842, 1719, 1556, 1460, 1440, 1420, 1372, 1327, 1270, 1137, 1063, 1008, 970, 842, 616 cm ^-1

D. 40 ml of a 25% solution of diisobutylaluminum hydride in toluene are added dropwise to a solution of 7 g of methyl 2-iodo-3-methoxypyridine-6-carboxylic acid in 95 ml of toluene and 50 ml of tetrahydrofuran at -70 ° C. The reaction mixture is stirred at -70 ° C for 30 minutes, warmed to -5 ° C within two hours and stirred at this temperature for 2 hours. The reaction mixture is cooled to -70 ° C., 20 ml of isopropanol and 20 ml of water are added in succession and the mixture is stirred at room temperature for three hours. The precipitate is filtered off with kieselguhr, the filter residue is washed with dichloromethane and the filtrate is concentrated. 6.54 g of 6-hydroxymethyl-2-iodo-3-methoxypyridine with a melting point of 106-108 ° C. are obtained.
IR (CHCl ₃ ): 3600, 3440 (broad), 2970, 2920, 2820, 1585, 1555, 1460, 1425, 1360, 1284, 1135, 1070, 1010, 820 cm ^-1

E. 175 g of manganese dioxide are added to a solution of 29 g of 6-hydroxymethyl-2-iodo-3-methoxypyridine in 600 ml of toluene and the suspension is heated with stirring and reflux for three hours on a water separator. The reaction mixture is filtered, the filter residue is washed with dichloromethane, the filtrate is dried over sodium sulfate and concentrated. The crude product is chromatographed on silica gel with hexane / 0-25% ethyl acetate. 12.9 g of 2-iodo-3-methoxypyridine-6-aldehyde with a melting point of 118-121 ° C. are obtained.
IR (CHCl ₃ ): 2985, 2920, 2830, 1698, 1550, 1455, 1417, 1380, 1312, 1270, 1120, 1058, 1003, 865, 825 cm ^-1

F. 680 mg of finely chopped zinc foil (Aldrich 0.25 mm thick, 99.999%) in 1 ml of absolute tetrahydrofuran is heated to 65 ° C. for one minute with 80 mg of 1.2 dibromoethane, cooled to 25 ° C., mixed with 40 μl of chlorotrimethylsilane and Stirred for 15 minutes. A solution of 2.3 g of methyl 3-iodobutyrate in 5 ml of absolute tetrahydrofuran is added dropwise to this activated zinc at 30 ° C. and the mixture is stirred at 35-40 ° C. for 16 hours. 4.3 ml of the 2-methoxycarbonylpropylzinc iodide solution thus obtained are added dropwise at -20 ° C. to a solution of 430 mg of copper I and 430 mg of lithium chloride in 1 ml of tetrahydrofuran. The reaction mixture is stirred for 5 minutes at 0 ° C, cooled again to -20 ° C, with a solution of 1.1 g of 2-iodo-3-methoxypyridine-6-aldehyde in 2 ml of tetrahydrofuran and 2 ml of dichloromethane and 1.9 ml of boron trifluoride-ethyl ether complex were added, the mixture was stirred at 0 ° C. for three hours and at room temperature for 20 hours. The reaction mixture is poured into saturated ammonium chloride solution, the precipitate is filtered off with kieselguhr, the filter residue is washed with ethyl acetate, the organic phase is separated off and the water phase is shaken three times with ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and the crude product is chromatographed on silica gel with hexane / 0-20% ethyl acetate. 1.11 g of (5RS) -5-hydroxy- 5- (2-iodo-3-methoxy-6-pyridyl) pentanoic acid methyl ester are obtained as an oil.
IR (film): 3430 (wide), 2940, 2860, 1727, 1550, 1456, 1425, 1362, 1285, 1200, 1063, 1005, 825, 615 cm ^-1

G. Under the conditions of Example 16E, 9.98 g of (5RS) -5-hydroxy-5- (2-iodo-3-methoxy-6-pyridyl) pentanoic acid methyl ester are reacted with 43 g of manganese dioxide for 6 hours, processed and the Chromatograph crude product on silica gel with hexane / 0-35% ethyl acetate. 4.3 g of methyl 5- (2-iodo-3-methoxy-6-pyridyl) -5-oxopentanoate of melting point 111 ° C. are obtained.
IR (CHCl ₃ ): 2990, 2940, 2842, 1724, 1690, 1552, 1455, 1418, 1360, 1303, 1124, 1060, 1005, 827 cm ^-1

H. To a solution of 3.87 g of 5- (2-iodo-3-methoxy-6-pyridyl) -5-oxopentanoic acid methyl ester and 1.87 ml of methyl acrylate in 10 ml of dimethylformamide are 244 mg of palladium acetate, 3.66 g of potassium carbonate and 3.4 g of tetrabutylammonium bromide were added and the suspension was heated to 100 ° C. for 5 hours with stirring and under an argon atmosphere. The solvent is removed in vacuo, the residue is mixed with water, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated. The crude product is chromatographed on silica gel with hexane / 0-15% ethyl acetate. 1.89 g of methyl 5- {3-methoxy-2- [2-methoxycarbonyl- (1E) -1-ethenyl] -6-pyridyl} -5-oxopentanoate are obtained, melting point 87-89 ° C.
IR (CHCl ₃ ): 2943, 2840, 1715, 1688, 1640, 1565, 1460, 1433, 1362, 1312, 1274, 1165, 1102, 1010, 883 cm ^-1

I. Under the conditions of Example 1C, a solution of 1.89 g of methyl 5- [3-methoxy-2- (2-methoxycarbonyl- (1E) -1-ethenyl) -6-pyridyl] -5-oxopentane is dissolved in 75 ml of methanol and 15 ml of tetrahydrofuran are hydrogenated and processed in the presence of 400 mg of 10% palladium catalyst. 1.9 g of 5- [3-methoxy-2- (2-methoxycarbonylethyl) -6-pyridyl] - (5RS) -5-hydroxype-ntanoic acid methyl ester are obtained as an oil.
IR (film): 3440 (wide), 2948, 2840, 1720, 1580, 1463, 1435, 1364, 1263, 1202, 1165, 1112, 1018, 988, 833 cm ^-1

J. To a solution of 470 mg of 5- [3-methoxy-2- (2-methoxycarbonylethyl) -6-pyridyl] - (5RS) -5-hydroxypentanoic acid methyl ester in 50 ml of dichloromethane under an argon atmosphere at 0 ° C., 2.9 g Collins reagent added and the mixture stirred for 2 hours at room temperature. The mixture is then diluted with hexane, admixed with kieselguhr until it forms a pulp, filtered through kieselguhr and washed with ethyl acetate. The filtrate is concentrated and the crude product is chromatographed on silica gel with hexane / 0-10% ethyl acetate. 337 mg of 5- [3-methoxy-2- (2-methoxycarbonylethyl) -6-pyridyl] -5-oxopentanoic acid methyl ester of melting point 64-66 ° C. are obtained.
IR (CHCl ₃ ): 2950, 2840, 1725, 1685, 1568, 1460, 1434, 1259, 1110, 1015 cm ^-1

K. A solution of 330 mg of 5- [3-methoxy-2- (2-methoxycarbonylethyl) -6-pyridyl] -5-oxopentanoic acid methyl ester in 3 ml of 48% hydrobromic acid is refluxed for 13 hours. The hydrobromic acid is distilled off, the residue is dissolved in water, adjusted to pH 4 with concentrated ammonia solution, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated. 190 mg of 5- [2- (2-carboxyethyl) -3-hydroxy-6-pyridyl] -5-oxopentanoic acid are obtained as a crude product with a melting point of 134-136 ° C. 180 mg of this crude product are dissolved in 5 ml of methanol, 60 mg of Amberlyst 15 are added and the mixture is stirred at room temperature for 16 hours. The reaction mixture is filtered through kieselguhr, the filter residue is washed with ethyl acetate, the filtrate is concentrated and the crude product is chromatographed on silica gel with hexane / 0-15% ethyl acetate. 75 mg of methyl 5- [3-hydroxy-2- (2-methoxycarbonylethyl) -6-pyridyl] -5-oxopentanoate are obtained as a yellow oil.
IR (CHCl ₃ ): 3300 (broad), 2945, 2840, 1730, 1680, 1590, 1568, 1433, 1412, 1283, 1094, 1020, 988, 835 cm ^-1

L. Under the conditions of Example 1D, 70 mg of 5- [3-hydroxy-2- (2-methoxycarbonylethyl) -6-pyridyl] -5-oxopentanoic acid methyl ester with 58 mg (1E) -6-bromo-1- (4- implemented methoxyphenyl) -1-hexene, processed and the crude product chromatographed on silica gel with hexane / 0-5% ethyl acetate. 52 mg of 5- {2- (2-methoxycarbonylethyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6 - pyridyl} - 5-oxopentanoic acid methyl ester are obtained as an oil.
IR (CHCl ₃ ): 2943, 1727, 1684, 1605, 1567, 1510, 1450, 1435, 1170, 1105, 1014, 965 cm ^-1

M. Under the conditions of Example 3C, 52 mg of 5- {2- (2-methoxycarbonylethyl) -3-6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6-pyridyl} -5-oxopentanoic acid methyl ester in 1.4 ml of methanol is saponified with 0.5 ml of 2N sodium hydroxide solution and processed. 30 mg of the title compound of melting point 99-102 ° C. are obtained.
IR (KBr): 3420 (broad), 2940, 1705, 1695, 1607, 1572, 1515, 1458, 1335, 1248, 1220, 1380, 1110, 1038, 1012, 970, 846, cm ^-1

Example 17 5- {2- (2-Carboxyethyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6-pyrid-yl} - (5RS) -5- hydroxypentanoic acid

A solution of 20 mg of 5- {2- (2-carboxyethyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] - 6-pyridyl} -5-oxopentanoic acid in 0.9 ml of dioxane and 0.1 ml of water are mixed with 6.5 mg of sodium borohydride and stirred at room temperature for 2 hours. The reaction mixture is mixed with ice water, acidified with glacial acetic acid, shaken out with dichloromethane, the organic phase dried over sodium sulfate and concentrated. The crude product is dissolved in 0.6 ml of methanol, 0.3 ml of 2N sodium hydroxide solution is added and the mixture is stirred for 48 hours at room temperature. The reaction mixture is concentrated, acidified to pH 3 with 2N sulfuric acid, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated. 15 mg of the title compound are obtained as a colorless oil.
IR (CHCl ₃ ): 3610, 3440 (broad), 2970, 1715, 1605, 1585, 1564, 1510, 1440, 1410, 1155, 1172, 1040, 967, 928, 875 cm ^-1

Example 18 3- {6- [2- (3-carboxyphenyl) - (1E) -1-ethenyl] -3- [6- (4-methoxyphenyl) - (5E) -5 - hexenyloxy] -2- pyridyl} propionic acid

A. Under the conditions of Example 16 H, a solution of 20 g of 2-iodo-3-methoxypyridine-6-aldehyde in 100 ml of dimethylformamide in the presence of 1.73 g of palladium acetate, 26.1 g of potassium carbonate and 23.8 g of tetrabutylammonium bromide reacted with 33.5 ml of methyl acrylate, processed and the crude product chromatographed on silica gel with hexane / 0-50% ethyl acetate. 11.66 g of methyl 3- (6-formyl-3-methoxy-2-pyridyl) - (2E) -2-propenate are obtained, melting point 132-134 ° C.
IR (CHCl ₃ ): 2945, 2840, 1720, 1700, 1641, 1564, 1463, 1435, 1315, 1305, 1270, 1165, 1103, 1014, 884 cm ^-1

B. Under the conditions of Example 1C, a solution of 11 g of methyl 3- (6-formyl-3-methoxy-2-pyridyl) - (2E) -2-propenate in 140 ml of tetrahydrofuran and 40 ml of methanol in the presence of 1. 2 g of 10% palladium catalyst on activated carbon hydrogenated and processed. 11 g of methyl 3- (6-hydroxymethyl-3-methoxy-2-pyridyl) propionate are obtained as an oily crude product, which is reacted and processed under the conditions of Example 16E with 78 g of manganese dioxide for 2 1/2 hours. 8.92 g of methyl 3- (6-formyl-3-methoxy-2-pyridyl-propionate) of melting point 95-97 ° C. are obtained.
IR (CHCl ₃ ): 2940, 2838, 1725, 1695, 1564, 1460, 1432, 1323, 1267, 1108, 1015, 828 cm ^-1

C. 8.8 g of methyl 3- (6-formyl-3-methoxy-2-pyridyl) propionate are reacted and processed in 114 ml of 48% hydrobromic acid under the conditions of Example 16 K. 4.7 g of 3- (6-formyl-3-hydroxy-2-pyridyl) propionic acid are obtained as crude product, which is dissolved in 350 ml of methanol for further reaction and in the presence of 14.4 g of Amberlyst for 15 hours at room temperature is stirred. The methanol is removed in vacuo, the residue is stirred with concentrated ammonia solution, filtered through diatomaceous earth and the filter residue is washed with concentrated ammonia solution. The filtrate is neutralized with concentrated hydrochloric acid, adjusted to pH 5 with dilute hydrochloric acid, extracted with ethyl acetate, the organic phase dried over sodium sulfate and concentrated. The crude product is chromatographed on silica gel with hexane / 0-20% ethyl acetate. 2.5 g of methyl 3- (6-formyl-3-hydroxy-2-pyridyl) propionate of melting point 92-95 ° C. are obtained.
IR (CHCl ₃ ): 3220 (broad), 2950, 2825, 1702, 1685, 1568, 1460, 1440, 1370, 1097, 1034, 928, 840 cm ^-1

D. Under the conditions of Example 1D, 510 mg of methyl 3- (6-formyl-3-hydroxy-2-pyridyl) propionate with 730 mg of (1E) -6-bromo-1- (4-methoxyphenyl) -1-hexene implemented, processed and the crude product chromatographed on silica gel with hexane / 0-10% ethyl acetate. 284 mg of methyl 3- {6-formyl-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionate of melting point 66-69 ° C. are obtained.
IR (CHCl ₃ ): 2940, 2830, 1725, 1696, 1605, 1564, 1509, 1413, 1322, 1173, 1108, 1030, 967, 830 cm ^-1

E. 110 mg of sodium hydride dispersion (60%, Fluka) are added to 2.4 ml of absolute dimethyl sulfoxide and the mixture is stirred at 65 ° C. for 1 hour under an argon atmosphere. 2.15 ml of this solution are added at room temperature to a solution of 668 mg of 3-carboxybenzyltriphenylphosphonium bromide in 1.75 ml of absolute dimethyl sulfoxide and the mixture is stirred for 30 minutes at room temperature. A solution of 280 mg of 3- {6-formyl-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionic acid methyl ester in 1 ml of dimethyl sulfoxide is then added and the mixture is added under an argon atmosphere Stirred for 16 hours at room temperature. For the esterification, 0.13 ml of iodomethane are added and the mixture is stirred at room temperature for a further 16 hours. The reaction mixture is poured into ice water, shaken with ethyl acetate, the organic phase dried over sodium sulfate and concentrated. 206 mg of 3- {6- [2- (3-methoxycarbonylphenyl) - (1E / Z) -1-ethenyl] -3- [6- (4-methoxyphenyl -) - (5E) -5-hexenyloxy] - 2-pyridyl} -propionic acid methyl ester obtained as a colorless oil, which is separated into the E and Z components by means of high pressure liquid chromatography on reversed phase silica gel (Nova-Pak HR C18) with methanol / water = 9/1. 66 mg of 3- {6- [2- (3-methoxycarbonylphenyl) - (1E) -1-ethenyl] -3- [6- (4-methoxyphenyl -) - (5E) -5-hexenyloxy] -2- methyl pyridyl} propionate melting point 81-83 ° C and 81 mg 3- {6- [2- (3-methoxycarbonylphenyl) - (1Z) -1-ethenyl] -3- [6- (4-methoxyphenyl -) - ( 5E) -5-hexenyloxy] -2-pyridyl} propionic acid methyl ester obtained as a colorless oil.
(1E) connection:
IR (CHCl ₃ ): 2925, 2855, 1720, 1608, 1575, 1510, 1455, 1290, 1175, 1030, 967 cm ^-1
(1Z) connection:
IR (film): 2945, 2918, 2845, 1720, 1607, 1575, 1510, 1407, 1435, 1285, 1247, 1173, 1115, 1033, 966, 837, 757 cm ^-1

F. Under the conditions of Example 3C, 62 mg of 3- {6- [2- (3-methoxycarbonyl phenyl) - (1E) -1-ethenyl] -3- [6- (4-methoxyphenyl) - (5E) - 5-hexenyloxy] -2-pyridyl} - methyl propionate in 2.5 ml of methanol and 1 ml of tetrahydrofuran saponified with 1.8 ml of 2N sodium hydroxide solution and processed. The residue is stirred with methanol and the crystals are suction filtered. 26 mg of the title compound are obtained as colorless crystals with a melting point of 193-195 ° C.
IR (KBr): 3420 (broad), 2940, 1710, 1685, 1605, 1575, 1510, 1458, 1285, 1245, 1175, 1118, 1035, 963, 820, 756 cm ^-1

Example 19 3- {6- [2- (3-carboxyphenyl) - (1Z) -1-ethenyl] -3- [6- (4-methoxyphenyl) - (5E) -5 - hexenyloxy] -2- pyridyl} propionic acid

Under the conditions of Example 3C, 82 mg of 3- {6- [2- (3-methoxycarbonylphenyl) - (1Z) -1-ethenyl] -3- [6- (4-methoxyphenyl) - (5E) -5- hexenyloxy] -2 - pyridyl} -propion acid methyl ester in 2.5 ml of methanol and 1 ml of tetrahydrofuran with 2 ml of 2N sodium hydroxide solution and prepared. 69 mg of the title compound are obtained as a colorless oil.
IR (film): 3500-2300, 1730, 1705, 1604, 1572, 1460, 1374, 1172, 1117, 1036, 965, 840 cm ^-1

Example 20 3- {6-Carboxy-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionic acid

A. Under the conditions of Example 1B, a solution of 22 g of 2-iodo-3-methoxypyridine-6-carboxylic acid methyl ester in 50 ml of dimethylformamide in the presence of 5.3 g of bis-triphenylphosphine palladium-II-chloride, 25.9 g of potassium carbonate and 23.4 g of tetrabutylammonium bromide reacted with 12.6 g of methyl acrylate, processed and the crude product chromatographed on silica gel with hexane / 0-30% ethyl acetate. There are 11 g of 3- (3-methoxy-6-methoxycarbonyl-2-pyridyl) - (2E) -2-propenoic acid methyl ester of melting point 123-126 ° C.
IR (CHCl ₃ ): 3005, 2960, 2850, 1725, 1715, 1648, 1577 1470, 1434, 1333, 1282, 1174, 1142, 1110, 1023, 847 cm ^-1

B. Under the conditions of Example 1C, a solution of 11 g of methyl 3- (3-methoxy-6-methoxycarbonyl-2-pyridyl) - (2E) -2-propenate in 600 ml of methanol in the presence of 2.2 g of 10% Palladium catalyst hydrogenated on activated carbon, processed and the crude product chromatographed on silica gel with hexane / 0-25% ethyl acetate. 8 g of 3- (3-methoxy-6-methoxycarbonyl-2-pyridyl) -propionic acid methyl ester of melting point 98-100 ° C. are obtained.
IR (CHCl ₃ ): 2960, 2855, 1730, 1720, 1575, 1468, 1434, 1336, 1140, 1116, 1023, 930, 845 cm ^-1

C. 6.5 g of methyl 3- (3-methoxy-6-methoxycarbonyl-2-pyridyl) propionate are reacted and processed in 60 ml of 48% hydrobromic acid under the conditions of Example 16 K. 4.1 g of 3- (6-carboxy-3-hydroxy-2-pyridyl) propionic acid with a melting point of 210-212 ° C. are obtained.
IR (KBr): 3420, (broad), 3330-2050, 1695, 1635, 1595, 1542, 1375, 1298, 1261, 1158, 1102, 980, 953, 880, 799 cm ^-1

D. 3.5 g of 3- (6-carboxy-3-hydroxy-2-pyridyl) propionic acid are suspended in 25 ml of toluene, 32 ml of N, N-dimethylformamide di-tert-butyl acetal are added and the mixture is left for one hour heated to 75-80 ° C (bath temperature). The reaction mixture is washed with water, 10% sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel with hexane / 0-15% ethyl acetate. 1.65 g of tert-butyl 3- (6-tert-butoxycarbonyl-3-hydroxy-2-pyridyl) propionate of melting point 172-174 ° C. are obtained.
IR (KBr): 2980, 2923, 1726, 1717, 1575, 1370, 1300, 1258, 1152, 1100, 1010, 848 cm ^-1

E. Under the conditions of Example 1D, 440 mg of tert-butyl 3- (6-tert-butoxycarbonyl-3-hydroxy-2-pyridyl) propionate are mixed with 367 mg of (1E) -6-bromo-1- ( 4-methoxy phenyl) -1-hexene reacted, processed and the crude product chromatographed on silica gel with hexane / 0-8% ethyl acetate. 350 mg of tert-butyl 3- {6-tert-butoxycarbonyl-3- [6- (4-methoxyphenyl) - (SE) -5-hexenyloxy] -2-pyridyl} -propionate are obtained as an oil.
IR (CHCl ₃ ): 2980, 2940, 1720, 1610, 1576, 1510, 1454, 1370, 1305, 1244, 1147, 1113, 1033, 970, 848 cm ^-1

F. A solution of 100 mg of tert-butyl 3- {6-butoxycarbonyl-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionate in 5 ml of methanol is heated under reflux with 5 ml of 6N sodium hydroxide solution for 24 hours. The methanol is distilled off in vacuo, the alkaline solution is acidified to pH 2 with 2N sulfuric acid and extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated. 80 mg of the title compound of melting point 120-123 ° C. are obtained.
IR (KBr): 3005, 2930, 1730, 1605, 1578, 1540, 1512, 1460, 1365, 1280, 1248, 1175, 1118, 1038, 963, 840, 798, 761 cm ^-1

Example 21 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2- (4-carboxymethylpheny-l) -ethynyl] -2- pyridyl} propionic acid

A. A solution of 100 g of 4-bromophenylacetic acid in 1.5 l of methanol is mixed with 232 g of Amberlyst 15 and the suspension is stirred for 48 hours at room temperature. The reaction mixture is suctioned off over kieselguhr, the filter residue is washed with dichloromethane and the filtrate is concentrated. The residue is taken up in ethyl acetate, washed with 10% sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated. 106 g of 4-bromophenylacetic acid methyl ester are obtained as an oil.
IR (CHCl ₃ ): 3000, 2852, 1722, 1593, 1486, 1435, 1340, 1255, 1160, 1070, 1010, 832 cm ^-1

B. A solution of 20 g methyl 4-bromophenylacetate and 10.3 g trimethyl silylacetylene in 650 ml of triethylamine is in the presence of 1.46 g of bis-triphenylphos phinpalladium-II-chloride and 227 mg copper-i-iodide heated under reflux for 5 hours. The The reaction mixture is concentrated, the residue between water and ethyl acetate distributed, the organic phase washed with saturated saline, over sodium dried sulfate and concentrated. The residue is on silica gel with hexane / 0-5% Chromatographed ethyl acetate. There are 17.1 g of 4- (2-trimethylsilylethynyl) phenylacetic acid Acid methyl ester obtained as an oily crude product.

C. A solution of 10 g of methyl 4- (2-trimethylsilylethynyl) -phenylacetate in 950 ml Tetrahydrofuran is at 0 ° C with 45 ml of a 1 molar solution of tetrabutyl ammonium fluoride added in tetrahydrofuran. The reaction mixture is 15 minutes stirred at 0 ° C and 2 hours at room temperature and then concentrated. Of the The residue is partitioned between water and ethyl acetate, the organic phase over Dried sodium sulfate, concentrated and the residue on silica gel with hexane / 0-7% Chromatographed ethyl acetate. There are 5.6 g of 4-ethynylphenylacetate as Obtain oily crude product.  

D. Under the conditions of Example 5A, 5 g of the crude methyl 4-ethynylphenylacetic acid are reacted with 7.9 g of methyl 3- (3-hydroxy-6-iodo-2-pyridyl) propionate, processed and the crude product on silica gel with hexane / Chromatographed 0-50% ethyl acetate. 3.6 g of methyl 3- {3-hydroxy-6- [2- (4-methoxycarbonylmethylphenyl) -ethynyl] -2-pyridyl} propionate of melting point 122-125 ° C. are obtained.
IR (CHCl ₃ ): 2270 (broad), 2960, 2220, 1735, 1713, 1580, 1512, 1458, 1415, 1371, 1262, 1171, 1108, 1018, 840 cm ^-1

E. Under the conditions of Example 1D, 600 mg of 3- {3-hydroxy-6- [2- (4-methoxycarbonylmethylphenyl) -ethynyl] -2-pyridyl} -propionic acid methyl ester with 460 mg of (1E) -6-bromo-1 - (4-methoxyphenyl) -1-hexene reacted, processed and the crude product chromatographed on silica gel with hexane / 0-10% ethyl acetate. There are 504 mg of 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2- (4-methoxycarbonylmethylph-enyl) -ethynyl] -2-pyridyl} -propionic acid methyl ester as Get oil.
IR (CHCl ₃ ): 3000, 2950, 2840, 2220, 1732, 1610, 1575, 1510, 1452, 1283, 1244, 1178, 1117, 1035, 970, 845, 827 cm ^-1

F. Under the conditions of Example 3C, 460 mg of 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2- (4-methoxycarbonylmethylphenyl) ethynyl] -2- p-yridyl} - methyl propionate in 14 ml of methanol and 6 ml of tetrahydrofuran with 11.3 ml of 2N sodium hydroxide solution and prepared. 352 mg of the title compound are obtained as a foam.
IR (KBr): 3420 (wide), 2930, 2830, 2210, 1732, 1708, 1605, 1575, 1510, 1450, 1245, 1178, 1110, 1032, 975, 822, 805 cm ^-1

Example 22 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2- (4-carboxymethylpheny-l) ethyl] -2- pyridyl} propionic acid

A. Under the conditions of Example 14A, a solution of 500 mg of methyl 3- {3-hydroxy-6- [2- (4-methoxycarbonylmethylphenyl) ethyl] -2-pyridyl} propionate in 5 ml of methanol in the presence of 50 mg 10% palladium catalyst hydrated on activated carbon and processed. The crude product is chromatographed on silica gel with hexane / 0-30% ethyl acetate. 266 mg of methyl 3- {3-hydroxy-6- [2- (4-methoxycarbonylmethylphenyl) ethyl] -2-pyridyl} propionate are obtained, melting point 90-91 ° C.
IR (CHCl ₃ ): 3300 (broad), 2955, 1730, 1715, 1467, 1440, 1368, 1258, 1114, 1110, 1015 cm ^-1

B. Under the conditions of Example 1D, 235 mg of 3- {3-hydroxy-6- [2- (4-methoxycarbonylmethylphenyl) ethyl] -2-pyridyl} -piopionic acid methyl ester with 145 mg (1E) -6-bromo-1 - (4-methoxyphenyl) -1-hexene reacted, processed and the crude product chromatographed on silica gel with hexane / 0-10% ethyl acetate. There are 137 mg of 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2-4-methoxycarbonylmethylphenyl) ethyl] -2-pyridyl} -piopionic acid as an oil receive.
IR (CHCl ₃ ): 2940, 1730, 1608, 1580, 1508, 1458, 1173, 1117, 1030, 968 cm ^-1

C. Under the conditions of Example 3C, 100 mg of 3- {3- [6- (4-methoxyphenyl) - (SE) -5-hexenyloxy] -6- [2- (4-methoxycarbonylmethylphenyl) ethyl] -2- pyr-idyl} - methyl propionate in 3 ml of methanol and 2.4 ml of 2N sodium hydroxide solution and prepared. 72 mg of the title compound are obtained as an oil.
IR (CHCl ₃ ): 2928, 2860, 1715, 1608, 1510, 1460, 1175, 1130, 967 cm ^-1

Example 23 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2- (4-benzenesulfonamidoc-arbonylphenyl) ethynyl] -2-pyridyl} propionic acid

A. 5 g of 4-iodobenzoic acid are added to a solution of 3.3 g of benzenesulfonamide, 2.68 g of 4-dimethylaminopyridine and 4.04 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide in 100 ml of dichloromethane, and the suspension 18 Stirred for hours at room temperature. The reaction mixture is diluted with 400 ml dichloromethane, washed successively with 400 ml portions of 10% hydrochloric acid, water and saturated sodium chloride solution, the organic phase dried over sodium sulfate and concentrated. The residue is slurried in diethyl ether / ethyl acetate = 1/1 and the crystals are filtered off with suction. 3.15 g of N-benzenesulfonyl-4-iodobenzoic acid amide with a melting point of 192-193 ° C. are obtained.
IR (KBr): 3280, 1695, 1585, 1430, 1340, 1245, 1178, 1070, 1002, 895, 822, 758, 682, 580, 560 cm ^-1

B. Under the conditions of Example 5A, 3.15 g of N-benzenesulfonyl-4-iodobenzoic acid are reacted with 1.3 g of trimethylsilylacetylene, processed and the crude product is chromatographed on silica gel with dichloromethane / 0-5% methanol. 3.1 g of N-benzenesulfonyl-4- (2-trimethylsilylethynyl) benzoic acid amide are obtained as an oil.
IR (film): 2915, 2825, 1700, 1605, 1575, 1508, 1458, 1371, 1115, 1040, 965, 840 cm ^-1

C. Under the conditions of Example 21C, a solution of 3.1 g of N-benzenesulfonyl 4- (2-trimethylsilylethynyl) benzoic acid amide in 200 ml tetrahydrofuran with 9.5 ml of a 1st molar solution of tetrabutylammonium fluoride in tetrahydrofuran and implemented processed. There are 3 g of N-benzenesulfonyl-4-enthinylbenzoic acid amide as a crude product receive.

D. Under the conditions of Example 5A, 1.31 g of the crude N-benzenesulfonyl-4-enthinylbenzoic acid amide is mixed with 1.9 g of 3- {6-iodo-3- [6- (4-methoxyphenyl) - (5E) -5 -hexenyloxy] - 2-pyridyl} -propionic acid methyl ester, processed and the crude product chromatographed on silica gel with dichloromethane / 0-5% methanol. 750 mg of methyl 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2- (4-benzenesulfonamidocar-bonylphenyl) ethynyl] -2-pyridyl} propionate are used as Get oil.
IR (CHCl ₃ ): 2940, 2210, 1728, 1696, 1604, 1572, 1509, 1450, 1420, 1350, 1280, 1170, 1110, 1070, 966, 890, 825 cm ^-1

E. Under the conditions of Example 3C, 20 mg of 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2- (4-benzenesulfonamidocarbonylphenyl) ethynyl] -2 -pyridyl} - methyl propionate in 0.7 methanol and 0.4 ml of 2N sodium hydroxide solution and prepared. 12 mg of the title compound are obtained as an oil.
IR (KBr): 3430 (broad), 2930, 2860, 1708, 1608, 1578, 1515, 1455, 1250, 1177, 1118, 1075, 1020, 892, 762, 690, 582 cm ^-1

Example 24 3- {6- [2- (4-carboxyphenyl- (1RS) - (2RS) -1,2-dihydroxyethyl] -3-decyloxy-2-p-yridyl} propionic acid

A. A solution of 500 mg methyl 3- {6- [2- (4-methoxycarbonylphenyl) -ethinyl] -3-decyloxy-2-pyridyl} propionate in 4.6 ml carbon tetrachloride, 4.6 ml acetonitrile and 7 ml water 303 mg of sodium periodate are added and the mixture is stirred at room temperature for 20 minutes. Then 2 mg of ruthenium IV oxide, hydrate are added and the mixture is stirred for 48 hours at room temperature. The reaction mixture is poured into water, extracted with dichloromethane, the organic phase is dried over sodium sulfate and concentrated. The crude product is chromatographed on silica gel with hexane / 0-5% ethyl acetate. 249 mg of methyl 3- {3-decyloxy-6- [2- (4-methoxycarbonylphenyl) -1,2-dioxoethyl-2-pyridyl} propionate are obtained as a yellow oil.
IR (film): 2930, 2860, 1730, 1695, 1565, 1455, 1440, 1410, 1363, 1344, 1280, 1215, 1108, 1020, 840 cm ^-1

B. A solution of 130 mg of 3- {3-decyloxy-6- [2- (4-methoxycarbonylphenyl) -1,2-dioxoethyl-2-pyridyl} propionic acid methyl ester in 8 ml of methanol is mixed with 22 mg of sodium borohydride and 18 hours stirred at room temperature. The reaction mixture is mixed with acetone, stirred for 30 minutes and concentrated. The residue is partitioned between water and ethyl acetate, the organic phase is dried over sodium sulfate and concentrated. 78 mg of 3- {3-decyloxy-6- [2- (4-methoxycarbonylphenyl) - (1RS) - (2RS) -1,2-dihydroxyethyl] -2-pyridyl} -piopionic acid methyl ester with a melting point of 88-92 ° C. receive.
IR (CHCl ₃ ): 3400 (broad), 2925, 2855, 1720, 1614, 1582, 1460, 1438, 1282, 1115, 1018 cm ^-1

C. Under the conditions of Example 3C, 70 mg of 3- {3-decyloxy-6- [2- (4-methoxycarbonylphenyl) - (1RS) - (2RS) -1,2-dihydroxyethyl] -2-pyridyl} - Propionic acid methyl ester in 2.5 ml of methanol and 1 ml of tetrahydrofuran with 1.9 ml of 2N sodium hydroxide solution and prepared. 49 mg of the title compound of melting point 162-164 ° C. are obtained.
IR (KBr): 3420-3020, 2920, 2850, 1720, 1685, 1612, 1580, 1460, 1422, 1320, 1288, 1198, 122, 1020, 935, 860 cm ^-1

Example 25 3- {6 [2- (5-carboxy-3-pyridyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hex-enyloxy] -2- pyridyl} propionic acid

A. Under the conditions of Example 21 B, 5 g of 5-bromnicotinic acid methyl ester are reacted with 2.43 g of trimethylsilylacetylene, processed and the crude product is chromatographed on silica gel with hexane / 0-5% ethyl acetate. 734 mg of methyl 5- (2-trimethylsilylethynyl) nicotinate are obtained as an oil.
IR (KBr): 3045, 2955, 2160, 1724, 1585, 1560, 1445, 1430, 1298, 1250, 1216, 1160, 1110, 1020, 980, 912, 840 cm ^-1

B. Under the conditions of Example 21C, 464 mg of 5- (2-trimethylsilylethynyl) - Methyl nicotate with 2 ml of a 1 molar solution of tetrabutylammonium fluoride implemented in tetrahydrofuran, processed and the residue on silica gel with hexane / 0-7% Chromatographed ethyl acetate. There are 196 mg of methyl 5-ethynyl nicotinate obtained as an oily crude product.

C. Under the conditions of Example 5A, 184 mg of the crude 5-ethynyl nicotinic acid methyl ester is mixed with 500 mg of 3- {6-iodo-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl } -Piopionic acid methyl ester, processed and the crude product chromatographed on silica gel with hexane / 0-30% ethyl acetate and subjected to complete purification of high pressure liquid chromatography on reversed phase silica gel (Nova-Pak HR C18) with acetonitrile / water = 75/25. 15 mg of 3- {6- [2- (5-methoxycarbonyl-3-pyridyl) -ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] - 2-pyridyl } - Methyl propionate obtained as an oil.
IR (CHCl ₃ ): 2957, 2930, 1728, 1605, 1573, 1510, 1455, 1292, 1112, 1030, 1015, 970 cm ^-1

D. Under the conditions of Example 3C, 15 mg of 3- {6- [2- (5-methoxycarbonyl-3-pyridyl) -ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy ] -2-pyridy-l} -propionic acid methyl ester in 0.5 ml of methanol and 0.5 ml of tetrahydrofuran saponified with 2 ml of 2N sodium hydroxide solution and processed. 10 mg of the title compound are obtained as the inner salt.
IR (KBr): 3440 (broad), 2930, 2855, 1575, 1580, 1458, 1262, 1110, 1030, 802 cm ^-1

Example 26 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2- (3-trifluoromethanesulfonamidophenyl) ethynyl] -2-pyridyl} propionic acid

A. 5.4 ml of trifluoromethanesulfonic anhydride are added dropwise to a solution of 5 g of 3-iodoaniline in 60 ml of chloroform and 3 g of triethylamine at 0-5 ° C., and the mixture is then heated under reflux for 8 hours. The reaction mixture is poured into water, shaken out with dichloromethane and the organic phase is concentrated. The residue is taken up in 3N sodium hydroxide solution and extracted with dichloromethane. The water phase is acidified to pH 2 with 10% sulfuric acid, shaken out with dichloromethane, the organic phase dried over sodium sulfate and concentrated. 6.3 g of N- (3-iodophenyl) -1,1,1-trifluoromethanesulfonamide with a melting point of 75-77 ° C. are obtained.
IR (CHCl ₃ ): 3360, 3280, 3120-3020, 2930, 2830, 1588, 1470, 1413, 1370, 1185, 1040, 1065, 1035, 925, 955, 825 cm ^-1

B. Under the conditions of Example 5A, 6.2 g of N- (3-iodophenyl) -1,1,1-trifluoromethanesulfonamide are reacted with 2.07 g of trimethylsilylacetylene, processed and the crude product on silica gel with hexane / 0-25% Chromatographed ethyl acetate. 2.72 g of N- [3- (2-trimethylsilylethynyl) phenyl] -1,1,1-trifluoromethanesulfonamido-d are obtained as a yellow oil.
IR (CHCl ₃ ): 3365, 2962, 2160, 1608, 1583, 1482, 1417, 1375, 1250, 1190, 1140, 1005, 980, 850 cm ^-1

C. Under the conditions of Example 21C, 2 g of N- [3- (2-trimethylsilylethynyl) - phenyl] -1,1,1-trifluoromethanesulfonamide with 6.9 ml of a 1 molar solution of Tetrabutylammoniumflorid implemented in tetrahydrofuran and processed. It will 387 mg of N- (3-ethynylphenyl) -1,1,1-trifluoromethanesulfonamide as an oily crude product receive.

D. Under the conditions of Example 5A, 370 mg of the crude N- (3-ethynylphenyl) - 1,1,1-trifluoromethanesulfonamide with 735 mg of 3- {6-iodo-3- [6- (4-methoxyphenyl) - ( 5E) -5-hexenyloxy] -2-pyridyl} propionic acid methyl ester, processed and the crude product chromatographed on silica gel with hexane / 0-20% ethyl acetate. There are 299 mg of methyl 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2- (3-trifluoromethanesulfonamidophenyl) ethynyl] -2-pyridyl} propionate as Get oil.
IR (CHCl ₃ ): 3360, 2930, 2850, 1730, 1605, 1580, 1510, 1451, 1420, 1373, 1195, 1142, 1114, 1035, 1005, 968 cm ^-1

E. Under the conditions of Example 3C, 100 mg of 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2- (3-trifluoromethanesulfonamidophenyl) ethynyl] -2 -pyridyl} - methyl propionate in 3 ml of methanol with 2.3 ml of 2N sodium hydroxide solution and prepared. 86 mg of the title compound are obtained as an oil.
IR (film): 3700-2300, 2215, 1710, 1604, 1575, 1508, 1450, 1290, 1372, 1325, 1140, 1035, 967, 898, 829, 790 cm ^-1

Example 27 5- {2- (2-Carboxyethyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6-pyrid-yl} pentanoic acid

A. Under the conditions of Example 5A, 2 g of methyl 3- (3-hydroxy-6-iodo-2-pyridyl) propionate are reacted with 0.8 g of methyl 4-pentynate, processed and the crude product on silica gel with hexane / 0- Chromatographed 30% ethyl acetate. 1.6 g of methyl 5- [3-hydroxy-2- (2-methoxycarbonylethyl) -6-pyridyl] -4-pentynate of melting point 119-121 ° C. are obtained.
IR (CHCl ₃ ): 3280 (broad), 2955, 2235, 1730, 1577, 1460, 1439, 1170, 1108, 1035, 985, 840 cm ^-1

B. Under the conditions of Example 14 A, a solution of 1 g of 5- [3-hydroxy-2- (2-methoxycarbonylethyl) -6-pyridyl] -4-pentynate in 10 ml of methanol in the presence of 100 mg of 10% strength Palladium catalyst on activated carbon hydrogenated and processed. Chromatograph the crude product on silica gel with hexane / 0-50% ethyl acetate. 665 mg of 5- [3-hydroxy-2- (2-methoxycarbonylethyl) -6-pyridyl] pentanoic acid methyl ester of melting point 92-95 ° C. are obtained.
IR (CHCl ₃ ): 3320 (broad), 2950, 2860, 1725, 1600, 1465, 1439, 1410, 1368, 1170, 1108 cm ^-1

C. Under the conditions of Example 1D, 490 mg of 5- [3-hydroxy-2- (2-methoxycarbonylethyl) -6-pyridyl] pentanoic acid methyl ester with 365 mg (1E) -6-bromo-1- (4-methoxyphenyl ) -1-hexene reacted, processed and the crude product chromatographed on silica gel with hexane / 0-10% ethyl acetate. 293 mg of 5- {2- (2-methoxycarbonylethyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6-pyridyl} pentanoic acid methyl ester are obtained as an oil.
IR (CHCl ₃ ): 2940, 2855, 1728, 1608, 1578, 1507, 1458, 1435, 1365, 1172, 1030, 965 cm} ¹

D. Under the conditions of Example 3C, 200 mg of 5- {2- (2-methoxycarbonylethyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6-pyridyl} pentanoic acid methyl ester in 6 ml of methanol and 1 ml of tetrahydrofuran saponified with 5 ml of 2N sodium hydroxide solution and processed. 170 mg of the title compound are obtained as a colorless oil.
IR (CHCl ₃ ): 2930, 2860, 2500 (broad), 1710, 1605, 1580, 1507, 1460, 1221, 1172, 1125, 1030, 965 cm ^-1

Example 28 3- {6- (5-Hydroxy-1-pentinyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2 - pyridyl} propionic acid

A. Under the conditions of Example 5A, 5 g of methyl 3- (3-hydroxy-6-iodo-2-pyridyl) propionate are reacted with 1.37 g of 4-pentyn-1-ol, processed and the crude product on silica gel with hexane / 0-4% methanol chromatographed. 1.2 g of methyl 3- [3-hydroxy-6- (5-hydroxy-1-pentinyl) -2-pyridyl] propionate are obtained as a colorless oil.
IR (CHCl ₃ ): 3270, 2950, 2230, 1708, 1572, 1455, 1410, 1362, 1168, 1103, 938, 835 cm ^-1

B. Under the conditions of Example 1D, 400 mg of methyl 3- [3-hydroxy-6- (5-hydroxy-1-pentinyl) -2-pyridyl] propionate are mixed with 410 mg of (1E) -6-bromo-1- ( 4-methoxyphenyl) -1-hexane reacted, processed and the crude product chromatographed on silica gel with hexane / 0-27.5% ethyl acetate. 293 mg of methyl 3- {6- (5-hydroxy-1-pentynyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} - propionate are obtained as a colorless oil.
IR (CHCl ₃ ): 3440 (broad), 2940, 2230, 1727, 1606, 1572, 1507, 1448, 1295, 1172, 115, 1030, 965, 823 cm ^-1

C. Under the conditions of Example 3C, 152 mg of 3- {6- (5-hydroxy-1-pentinyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} -saponified with methyl propionate in 4.5 ml of 2N sodium hydroxide solution and processed. 147 mg of the title compound of melting point 115-117 ° C. are obtained.
IR (CHCl ₃ ): 3400 (broad), 2935, 2540 (broad), 2235, 1720, 1608, 1577, 1510, 1453, 1275, 1175, 1034, 968, 830 cm ^-1 .

Claims (33)

1. Pyridine derivatives of the general formula I wherein
· · · Symbolizes a single bond or a double bond,
m, n and r each represent a number from 0 to 5,
q represents the numbers 1 or 2,
U symbolizes a single bond or the grouping -CH ₂ -CH ₂ -, -CHOH-, -CO-, -CH = CH-, -C = C-, -CO-CO- or -CHOH-CHOH-,
V denotes a single bond, a phenyl radical or a pyridyl radical,
W represents a hydrogen atom, a halogen atom, an alkyl group having up to 4 carbon atoms, a trifluoromethyl group, an alkylsulfonylamino group, a trifluoromethylsulfonylamino group, an arylsulfonylaminocarbonyl group, a free, esterified or amidated carboxyl group, or a hydroxyl group,
X symbolizes a free, esterified or amidated carboxyl group,
Y represents an oxygen atom or a methylene group and
Z is a single bond if q denotes the number 2 or otherwise an alkyl group or alkylene group with a maximum of 8 carbon atoms or one optionally by alkyl groups with a maximum of 4 carbon atoms, alkoxy groups with a maximum of 4 carbon atoms, 1-oxoalkyl groups with a maximum of 4 carbon atoms, halogen atoms and / or trifluoromethyl groups substituted phenyl radical, phenoxy radical or styryl radical, and their salts with physiologically acceptable bases. 2. 3- {3- [6- (4-Methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionic acid. 3. 3- {3- [3- (4-Acetyl-3-methoxy-2-propylphenoxy) propoxy] -2-pyridyl} propionic acid. 4. 3- {6-iodo-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionic acid.   5. 3- {6-Acetyl-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionic acid. 6. 5- {2- (2-carboxyethyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6-pyrid-yl} -4- pentic acid. 7. 3- {6- [2- (3-carboxyphenyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2- pyridyl} propionic acid. 8. 3- {6- [2- (4-carboxyphenyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2- pyridyl} propionic acid. 9. 3- {6- [2- (4-carboxyphenyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2- pyridyl} propionic acid, bis-tris (hydroxymethyl) aminomethane salt. 10. 3- {6- [2-4-Carboxyphenyl) ethynyl] -3-decyloxy-2-pyridyl} propionic acid. 11. 3- {6- [2- (4-carboxyphenyl) ethynyl] -3- [3- (4-acetyl-3-methoxy-2-propylphenoxy) - propoxy] -2-pyridyl} propionic acid. 12. 3- {6- [2- (4-carboxyphenyl) ethynyl] -3 - [(3RS) -3,7-dimethyl-6-octenyloxy] -2- pyridyl} propionic acid. 13. 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- (2-phenylethynyl) -2-pyridyl} - propionic acid. 14. 3- {6- [2-3-Carboxyphenyl) -ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyl-oxy] - 2-pyridyl} propionic acid, bis-tris (hydroxymethyl) aminomethane salt. 15. 3- {6- [2- (4-carboxyphenyl) ethyl] -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2- pyridyl} propionic acid. 16. 1,10-bis- {2- (2-carboxyethyl) -6- [2- (4-carboxyphenyl) ethynyl] -3-pyridyloxy} - decan. 17. 5- {2- (2-carboxyethyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6-pyridyl} -5- oxopentanoic acid. 18. 5- {2- (2-carboxyethyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6-pyrid-yl} - (5RS) -5- hydroxypentanoic acid.   19. 3- {6- [2- (3-carboxyphenyl) - (1E) -1-ethenyl] -3- [6- (4-methoxyphenyl) - (5E) -5-- hexenyloxy] -2-pyridyl} propionic acid. 20. 3- {6- [2- (3-t-carboxyphenyl) - (1Z) -1-ethenyl] -3- [6 (4-methoxyphenyl) - (5E) -5-- hexenyloxy] -2-pyridyl} propionic acid. 21. 3- {6-Carboxy-3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2-pyridyl} propionic acid. 22. 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] 6- [2-4-carboxymethylphenyl) thinyl] - 2-pyridyl} propionic acid. 23. 3- {3- [6- (4-Methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2- (4-carboxymethyl) eth-yl] -2-pyridyl} propionic acid. 24. 3- {3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2- (4-benzenesulfonamidoc-arbonyl phenyl) ethynyl] -2-pyridyl} propionic acid. 25. 3- {6- [2- (4-carboxyphenyl) - (1RS) - (2RS) -1,2-dihydroxyethyl] -3-decyloxy-2 - pyridyl} - propionic acid. 26. 3 - {- 6- [2- (5-carboxy-3-pyridyl) ethynyl] -3- [6- (4-methoxyphenyl) - (5E) -5-h-exenyloxy] -2- pyridyl} propionic acid. 27. 3- {3- [6- (4Methoxyphenyl) - (5E) -5-hexenyloxy] -6- [2- (3-trifluoromethanesulfon-n amidophenyl) ethynyl] -2-pyridyl} propionic acid. 28. 5- {2- (2-carboxyethyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -6-pyrid-yl} - pentanoic acid. 29. 3- {6- (5-Hydroxy-1-pentynyl) -3- [6- (4-methoxyphenyl) - (5E) -5-hexenyloxy] -2 - pyridyl} - propionic acid. 30. Pharmaceutical preparations, characterized by a content of one or two pyridine Derivatives according to claims 1 to 29. 31. Pharmaceutical preparations according to claim 30 with leukotriene-B4 antagonistic Effect.   32. Process for the preparation of pyridine derivatives of the general formula I wherein
· · · Symbolizes a single bond or a double bond,
m, n and r each represent a number from 0 to 5,
q represents the numbers 1 or 2,
U symbolizes a single bond or the grouping -CH ₂ -CH ₂ -, -CHOH-, -CO-, -CH = CH- or -C = C-, -CO-CO- or -CHOH-CHOH-,
V denotes a single bond, a phenyl radical or a pyridyl radical,
W represents a hydrogen atom, a halogen atom, an alkyl group having up to 4 carbon atoms, a trifluoromethyl group, an alkylsulfonylamino group, a trifluoromethylsulfonylamino group, an arylsulfonylaminocarbonyl group, a free, esterified or amidated carboxyl group, or a hydroxyl group,
X symbolizes a free, esterified or amidated carboxyl group,
Y represents an oxygen atom or a methylene group and
Z is a single bond if q denotes the number 2 or otherwise an alkyl group or alkylene group with a maximum of 8 carbon atoms or one optionally by alkyl groups with a maximum of 4 carbon atoms, alkoxy groups with a maximum of 4 carbon atoms, 1-oxoalkyl groups with a maximum of 4 carbon atoms, halogen atoms and / or trifluoromethyl groups substituted phenyl radical, phenoxy radical or styryl radical, and their salts with physiologically acceptable bases, characterized in that in a manner known per se

• a) for the preparation of pyridine derivatives of the general formula I with Y in the meaning of an oxygen atom, a compound of the general formula II wherein m, p, r, U, V, W and X have the meaning given above in the presence of bases with a compound of the general formula III or IVQ- (CH₂) _n -Z ′ (III) Q- (CH₂) _n - Q (IV) where
  n has the meaning given above,
  Z 'is the same as Z, but is not a single bond and
  Q represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group, condenses, or
• b) for the preparation of pyridine derivatives of the general formula I with U in the meaning of a grouping -CO-, -CH = CH-, -C = C-, -CO-CO- or -CHOH-CHOH- a compound of the general formula V wherein
  · · · , M, n, p, q, X, Y and Z have the meaning given above and Q 'represents a halogen atom or a trifluoromethanesulfonyloxy group, with a compound of the formula VI, VII or VIII wherein
  p, r, V and W have the meaning given above and
  R 'represents lower alkyl radicals with a maximum of 4 carbon atoms, or
• c) for the preparation of pyridine derivatives of the general formula I with U in the meaning of the grouping -CH = CH- a compound of the general formula IX wherein
  · · · , M, n, q, X, Y and Z have the meaning given above, with a compound of the general formula XW- (CH₂) _r -V- (CH₂) _p -CH₂-P (C₆H₅) ₃ + Br - (X) in which p, r, V and W have the abovementioned meaning, condenses and, if appropriate, oxidizes an existing triple bond, reduces existing oxo groups, hydrogenates existing multiple bonds, hydrogenates existing hydroxyl groups, saponifies existing ester groups and / or esterifies existing carboxyl groups or into them Amides or salts transferred.

33. A process for the preparation of pyridine derivatives of the general formula II according to claim 32 with U in the meaning of a -C = C- or -CH ₂ -CH ₂ group, characterized in that a compound of the general formula XI wherein
· · · M, X and Q 'have the meaning given above, with a compound of the general formula XIIW- (CH₂) _r -V- (CH₂) _p -C≡CH (XII) wherein p, r, V and W have the abovementioned Have meaning, implemented and optionally hydrogenated the triple bond.